Abstract
BACKGROUND: Metabolic dysfunction–associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide and is strongly linked to obesity, type 2 diabetes, and cardiovascular disease. Growing evidence highlights the role of the gut–liver axis, particularly microbial metabolites such as the short-chain fatty acid (SCFA) butyrate, in MASLD pathophysiology. However, clinical data on butyrate levels and the abundance of butyrate-producing bacteria in MASLD patients remain inconsistent. OBJECTIVES: To systematically synthesize human evidence evaluating the associations between butyrate levels and butyrate-producing gut bacteria with MASLD presence and severity, as well as related metabolic comorbidities. METHODS: A systematic search was conducted in PubMed and Embase from inception to April 7, 2025, following PRISMA 2020 guidelines (PROSPERO registration CRD420251162439). Eligible studies included observational human research assessing fecal or plasma SCFA concentrations and/or the abundance of butyrate-producing taxa in adults with MASLD and related metabolic disorders. Study quality was appraised using the Newcastle–Ottawa Scale, and results were narratively synthesized due to heterogeneity across methods and outcomes. RESULTS: From 233 records, seven studies met inclusion criteria (2020–2025; n = 1,185). Most were cross-sectional or case–control designs of moderate to high quality (NOS 6–8/9). Individuals with MASLD generally exhibited lower fecal or serum butyrate concentrations and reduced abundance of Faecalibacterium prausnitzii, Eubacterium, and other butyrate-producing bacteria versus controls. These alterations were associated with hepatic steatosis, fibrosis, inflammation, and adverse metabolic profiles - higher BMI, insulin resistance, and dyslipidemia. Geographic and sex-related differences were also reported. CONCLUSIONS: This systematic review suggests that reduced butyrate availability and alterations in butyrate-producing gut taxa are associated with MASLD presence and severity and with adverse metabolic traits. However, substantial methodological heterogeneity and the observational design of available studies preclude causal inference. Larger, well-phenotyped, multicentre studies using standardized SCFA quantification, dietary and medication ascertainment, and functional microbiome profiling are needed to validate these findings and clarify their diagnostic and therapeutic implications. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13679-026-00694-8.